High-purity quinoline derivative and method for manufacturing same

ABSTRACT

Provided is a compound represented by formula (IV) or a salt thereof, wherein the content of the compound represented by formula (I) is 350 ppm by mass or less.

TECHNICAL FIELD

The present invention relates to a quinoline derivative and a method forproducing the same. More specifically, the present invention relates toa highly pure quinoline derivative and a production method forefficiently obtaining the quinoline derivative.

RELATED BACKGROUND ART

Quinoline derivatives represented by compound (IV):

are known to exhibit excellent antitumor activity (PTL 1).

PTLs 1, 2, 3, 4 and 5 disclose methods for producing these quinolinederivatives. Specifically, in the production method of PTL 1 (such asdescribed in Example 368), 4-amino-3-chlorophenol hydrochloride isreacted with 4-chloro-7-methoxy-quinoline-6-carboxamide (step A), phenylchloroformate is reacted with the obtained4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide and theresulting phenylN-{4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl}carbamate isisolated (step B), and then cyclopropylamine is further reacted with thecarbamate (step C) to obtain the target compound,4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide(hereunder referred to as “compound (IV)”), with a total yield of 25.5%for the three steps.

In the production methods described in PTL 2 (Reference Example 1) andPTL 4 (Production Example 1), cyclopropylamine is reacted with phenylN-{4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl}carbamate toobtain compound (IV), with a yield of 80.2%.

In the production methods described in PTL 2 (Reference Example 3), PTL3 (Example 4), PTL 4 (Production Example 3) and PTL 5 (Example 1a), thetarget compound (IV) is obtained by a single step from4-chloro-7-methoxy-quinoline-6-carboxamide, with a yield of 86.3% inPTLs 2 to 4 and a yield of 91.4% in PTL 5.

Subsequently, the production methods described in PTLs 1 to 5 will bespecifically described. The production method described in PTL 1(Example 368 and the like) is as the following formulas.

The reaction scheme for the production method in PTL 2 (ReferenceExample 1) and PTL 4 (Production Example 1) is as follows.

The production methods in PTL 2 (Reference Example 3), PTL 3 (Example4), PTL 4 (Production Example 3) and PTL 5 (Example 1a) have thefollowing reaction scheme.

CITATION LIST Patent Literature

-   [PTL 1] US2004/0053908-   [PTL 2] US2007/0004773-   [PTL 3] US2007/0037849-   [PTL 4] US2007/0078159-   [PTL 5] US2007/0117842

SUMMARY OF INVENTION Technical Problem

The present inventors have found that, in the case where a compoundrepresented by formula (IV) or a salt thereof is produced by use of theproduction methods described PTLs 1 to 5, the product contains acompound represented by formula (I), a compound represented by formula(A-1), a compound represented by formula (C-1), and the like asimpurities and that it is difficult to remove such impurities by acommon purification method such as chromatography and crystallization.

Thus an object of the present invention is to provide a highly purequinoline derivative with a small amount of impurities. Another objectof the present invention is to provide a production method suitable forlarge-scale production in order to obtain a highly pure quinolinederivative in a high yield.

Solution to Problem

The present inventors, as a result of intensive studies in considerationof the situation described above, have found a novel method forproducing the quinoline derivative described above, thereby havingcompleted the present invention. Thus, the present invention providesthe following [1] to [27]:

[1] A compound represented by formula (IV) or a salt thereof, whereinthe content of a compound represented by formula (I) is 350 ppm by massor less.

[2] A compound represented by formula (IV) or a salt thereof, whereinthe content of a compound represented by formula (I) is 183 ppm by massor less.

[3] A compound represented by formula (IV) or a salt thereof, whereinthe content of a compound represented by formula (A-1) is 60 ppm by massor less.

[4] A compound represented by formula (IV) or a salt thereof, whereinthe content of a compound represented by formula (I) is 350 ppm by massor less, and the content of a compound represented by formula (A-1) is60 ppm by mass or less.

[5] A compound represented by formula (IV) or a salt thereof, whereinthe content of a compound represented by formula (I) is 183 ppm by massor less, and the content of a compound represented by formula (A-1) is60 ppm by mass or less.

[6] A compound represented by formula (IV) or a salt thereof, whereinthe content of a compound represented by formula (C-1) is 0.10% by massor less.

[7] The compound represented by formula (IV) or a salt thereof accordingto any one of [1] to [6], wherein the content of the compoundrepresented by formula (IV) is 98.0% by mass or more.

[8] A composition wherein the content of a compound represented byformula (IV) or a salt thereof is 98.0% by mass or more, and the contentof a compound represented by formula (I) or a salt thereof is 350 ppm bymass or less.

[9] A composition wherein the content of a compound represented byformula (IV) or a salt thereof is 98.0% by mass or more, and the contentof a compound represented by formula (I) or a salt thereof is 183 ppm bymass or less.

[10] A composition wherein the content of a compound represented byformula (IV) or a salt thereof is 98.0% by mass or more, and the contentof a compound represented by formula (A-1) or a salt thereof is 60 ppmby mass or less.

[11] A composition wherein the content of a compound represented byformula (IV) or a salt thereof is 98.0% by mass or more, the content ofa compound represented by formula (I) or a salt thereof is 350 ppm bymass or less, and a content of a compound represented by formula (A-1)or a salt thereof is 60 ppm by mass or less.

[12] A composition wherein the content of a compound represented byformula (IV) or a salt thereof is 98.0% by mass or more, the content ofa compound represented by formula (I) or a salt thereof is 183 ppm bymass or less, and the content of a compound represented by formula (A-1)or a salt thereof is 60 ppm by mass or less.

[13] A composition wherein the content of a compound represented byformula (IV) or a salt thereof is 98.0% by mass or more, and the contentof a compound represented by formula (C-1) or a salt thereof is 0.10% bymass or less.

[14] A pharmaceutical comprising the compound according to any one of[1] to [7] or a salt thereof as an active ingredient.[15] A pharmaceutical comprising the composition according to any one of[8] to [13] as an active ingredient.[16] A pharmaceutical composition using the compound or a salt thereofaccording to any one of [1] to [7] as an active ingredient, wherein thepharmaceutical composition further comprises a pharmaceuticallyacceptable carrier.[17] A pharmaceutical composition comprising the composition accordingto any one of [8] to [13] as an active ingredient, wherein thepharmaceutical composition further comprises a pharmaceuticallyacceptable carrier.[18] An oral solid formulation comprising the compound or salt thereofaccording to [4] as an active ingredient, wherein the oral solidformulation further comprises a pharmaceutically acceptable carrier, andthe content of the compound represented by formula (I) is 0.06% by massor less.[19] An oral solid formulation comprising the composition according to[8] or [11] as an active ingredient, wherein the oral solid formulationfurther comprises a pharmaceutically acceptable carrier, and the contentof the compound represented by formula (I) is 0.06% by mass or less.[20] An oral solid formulation comprising the compound or salt thereofaccording to [5] as an active ingredient, wherein the oral solidformulation further comprises a pharmaceutically acceptable carrier, andthe content of the compound represented by formula (I) is 0.040% by massor less.[21] An oral solid formulation comprising the composition according to[9] or [12] as an active ingredient, wherein the oral solid formulationfurther comprises a pharmaceutically acceptable carrier, and the contentof the compound represented by formula (I) is 0.040% by mass or less.[22] A method for producing a compound represented by formula (IV)

or a salt thereof, comprising:

a step B of allowing a compound represented by formula (I)

or a salt thereof to react with a compound represented by formula (II-A)or formula (II-B)

wherein R¹ is a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₆₋₁₀ arylgroup, or a C₇₋₁₁ aralkyl group, wherein the C₁₋₆ alkyl group or theC₂₋₆ alkenyl group may have one to three substituents that may be thesame or different and are selected from the group consisting of ahalogen atom and a methoxy group, and wherein the C₆₋₁₀ aryl group orthe C₇₋₁₁ aralkyl group may have one to three substituents that may bethe same or different and are selected from the group consisting of ahalogen atom, a methyl group, a methoxy group, and a nitro group; and Xis a halogen atom,in the presence of a base to thereby obtain a compound represented byformula (III)

wherein R¹ is the same group as above, and

a step C of, after allowing the compound represented by formula (III)obtained in the step B to react without isolation with cyclopropylamine,precipitating and isolating a compound represented by formula (IV)

or a salt thereof by introducing a hydrous organic solvent to a reactionsolution.[23] A method for producing a compound represented by formula (IV)

or a salt thereof, comprising:

a step A of, after allowing a compound represented by formula (A-1)

to react with a compound represented by formula (A-2)

or a salt thereof in the presence of a base, precipitating and isolatinga compound presented by formula (I)

or a salt thereof from a reaction solution by introducing a hydrousorganic solvent to the reaction solution,

a step B of allowing the compound represented by formula (I)

or a salt thereof obtained in the step A to react with a compoundrepresented by formula (II-A) or formula (II-B)

wherein R¹ is a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₆₋₁₀ arylgroup, or a C₇₋₁₁ aralkyl group, wherein the C₁₋₆ alkyl group or theC₂₋₆ alkenyl group may have one to three substituents that may be thesame or different and are selected from the group consisting of ahalogen atom and a methoxy group, and wherein the C₆₋₁₀ aryl group orthe C₇₋₁₁ aralkyl group may have one to three substituents that may bethe same or different and are selected from the group consisting of ahalogen atom, a methyl group, a methoxy group, and a nitro group; and Xis a halogen atom,in the presence of a base to thereby obtain a compound represented byformula (III)

wherein R¹ is the same group as above, and

a step C of, after allowing the compound represented by formula (III)obtained in the step B to react without isolation with cyclopropylamine,precipitating and isolating a compound represented by formula (IV)

or a salt thereof by introducing a hydrous organic solvent to a reactionsolution.[24] The method according to [22] or [23] further comprising a step D ofconverting the compound represented by formula (IV) obtained in the stepC into a salt of the compound represented by formula (IV).[25] The method according to [24], wherein the salt obtained in the stepD is a methanesulfonate.[26] The method according to any one of [22] to [25], wherein the step Bis a step of allowing the compound represented by formula (I)

or a salt thereof to react with the compound represented by formula(II-A)

wherein R¹ is a C₆₋₁₀ aryl group that may have one to three substituentsthat may be the same or different and are selected from the groupconsisting of a halogen atom, a methyl group, a methoxy group, and anitro group; and X is a halogen atom,in the presence of a base to thereby obtain a compound represented byformula (III)

wherein R¹ is the same group as above.[27] The method according to any one of [22] to [26], wherein thecompound represented by formula (II-A) is phenyl chloroformate.

Advantageous Effects of Invention

According to the present invention, a high-yield and highly purecompound (IV) can be provided.

DESCRIPTION OF EMBODIMENTS

The symbols and terms used throughout the present specification will nowbe explained.

In the present specification, anhydrates, hydrates, and solvates areincluded by “a compound”. Also in the present specification,descriptions of “a compound (I)” and the like each mean a compound sameas “a compound represented by formula (I)” and the like.

In the present specification, “a compound or a salt thereof” refers to acompound or a salt thereof that comprises 90% by mass or more of thecompound and may comprise a starting material or a byproduct that may beformed as impurities. For example, “a compound represented by formula(IV) or a salt thereof” comprises 90% by mass or more of the compound(IV) or a salt thereof and may comprises a starting material such as acompound (I), a compound (A-1), and a byproduct such as a compound (C-1)that may be formed in each production step. Accordingly, “a compound ora salt thereof” in the present specification, which may comprise abyproduct and the like as impurities, has an aspect of “a composition”.In the case of expressing the content of impurities such as the compound(I), the compound (A-1), and the compound (C-1) herein, the content isbased on the total mass of the compound (IV) or a salt thereof.

In the present specification, “a pharmaceutical composition” refers to acomposition comprising a compound having a pharmacological effect or asalt thereof and a pharmaceutically acceptable carrier. An example ofthe compound having a pharmacological effect or a salt thereof is acompound (IV) or a salt thereof. Alternatively, “a formulation” meansthose that have been subjected to a treatment (such as sterilization andtableting) bringing them into a state in which they can be administeredto a subject in need thereof, as required, relative to pharmaceuticalcompositions. Alternatively, “a pharmaceutical” is one used for therapyor prophylaxis of a disease and includes any optional forms.

Also, the term “C₁₋₆ alkyl group” as used herein means a monovalentgroup derived by removing any one hydrogen from a C₁₋₆ aliphaticsaturated hydrocarbon, and it is a C₁₋₆ straight-chain or branched-chainsubstituent. Examples of C₁₋₆ alkyl groups include methyl, ethyl,1-propyl, 2-propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-butyl,2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl and 3-hexylgroups, with methyl, ethyl and 1-propyl groups being preferred.

The term “C₁₋₆ alkenyl group” as used herein means a monovalent groupderived by removing any one hydrogen from a C₁₋₆ aliphatic hydrocarbonwith an unsaturated bond, and it is a C₁₋₆ straight-chain orbranched-chain substituent. Examples of C₁₋₆ alkenyl groups include2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl and4-hexenyl groups, with 2-propenyl group being preferred.

The term “C₆₋₁₀ aryl group” as used herein refers to a C₆₋₁₀ aromaticcyclic hydrocarbon group. Examples of C₆₋₁₀ aryl groups include phenyl,1-naphthyl and 2-naphthyl groups, with phenyl group being preferred.

The term “C₇₋₁₁ aralkyl group” as used herein refers to a C7-11 aralkylgroup. Examples of C₇₋₁₁ aralkyl groups include benzyl andnaphthylmethyl groups, with benzyl group being preferred.

The term “halogen atom” as used herein refers to fluorine, chlorine,bromine or iodine atoms, and preferably a chlorine atom.

The term “base” as used herein may refer to an inorganic base such aslithium hydroxide, sodium hydroxide, potassium hydroxide, lithiumcarbonate, sodium carbonate, potassium carbonate, potassiumtert-butoxide, sodium tert-butoxide, sodium hydrogencarbonate, potassiumhydrogencarbonate or cesium carbonate; an organometallic reagent such asbutyllithium, methyllithium, lithium bistrimethylsilylamide, sodiumbistrimethylsilylamide or potassium bistrimethylsilylamide; a hydridesuch as lithium hydride, sodium hydride or potassium hydride; aheterocyclic compound such as imidazole, pyridine, dimethylpyridine,trimethylpyridine or 4-dimethylaminopyridine; or an organic amine suchas triethylamine, N,N-diisopropylethylamine or diazabicycloundecene.

Compound (I) or a salt thereof may be an anhydrate, a hydrate or asolvate, an example of a solvate being dimethyl sulfoxide solvate.

There are no particular restrictions on the salts of compound (I), andexamples of salts of compound (I) include inorganic acid salts, organicacid salts and acidic amino acid salts.

There are also no particular restrictions on salts of compound (IV), andexamples of salts of compound (IV) include inorganic acid salts, organicacid salts and acidic amino acid salts.

Preferred examples of inorganic acid salts include salts of hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.

Preferred examples of salts of organic acids include salts of aceticacid, succinic acid, fumaric acid, maleic acid, tartaric acid, citricacid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid,ethanesulfonic acid and p-toluenesulfonic acid, with methanesulfonicacid salts being preferred.

Preferred examples of acidic amino acid salts include salts of asparticacid and glutamic acid.

There are no particular restrictions on salts of compounds representedby formula (A-2), and examples include salts of inorganic acids such ashydrochloric acid and hydrobromic acid.

The production method of the invention will now be explained in greaterdetail.

Production Method 1: Method for Producing Compound (I) or it Salt (stepA)

Step A is a step in which compound (A-2) or a salt thereof is reactedwith compound (A-1) to obtain compound (I) or a salt thereof.

The reaction solvent is not particularly restricted so long as itdissolves the starting material and does not interfere with thereaction, and for example, it may be dimethyl sulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone or the like, with dimethyl sulfoxidebeing preferred.

Compound (A-2) or a salt thereof may be used at 1.0 to 2.0 equivalentswith respect to the number of moles of compound (A-1).

The base is not particularly restricted, and for example, it may be abase such as cesium carbonate, potassium t-butoxide or potassiumhydroxide, with potassium hydroxide being preferred. The base may beused at 1.5 to 2.0 equivalents with respect to the number of moles ofthe compound (A-2) or a salt thereof used in the reaction.

The reaction time will also, in general, differ depending on thestarting materials, solvent and other reagents used in the reaction, butit is preferably 5 to 100 hours and more preferably 10 to 30 hours.

The reaction temperature will likewise generally differ depending on thestarting materials, solvent and other reagents used in the reaction, butit is preferably from room temperature to the solvent refluxtemperature, more preferably 60° C. to 80° C. and even more preferably65° C. to 75° C.

Upon completion of the reaction, a water-containing organic solvent maybe introduced into the reaction mixture to precipitate and isolatecompound (I) or a salt thereof. The amount of water-containing organicsolvent introduced may be a 10 to 20-fold (v/w) volume with respect tothe mass of compound (A-1). Also, the water-containing organic solventused may be, for example, water/acetone (volume ratio: 50/50 to 80/20).

The compound (I) or a salt thereof can be obtained as an anhydrate, ahydrate, or a solvate by changing drying conditions, i.e., conditionssuch as temperature and the degree of pressure reduction.

Production Method 2: Method for Producing Compound (IV) or a SaltThereof (Steps B and C)

This method comprises a step in which compound (I) or a salt thereofobtained in production method 1 described above is reacted with compound(II) to obtain compound (III) (step B), and a step in which compound(III), as the activated form of compound (I), is reacted withcyclopropylamine without being isolated, to obtain compound (IV) or asalt thereof (step C). The term “compound (II)” is a general termreferring to the reagent for conversion of compound (I) to compound(III) as its activated form, and it is compound (II-A), compound (II-B)or another activating reagent.

The reaction solvent is not particularly restricted so long as it doesnot inhibit the reaction, and for example, N,N-dimethylformamide,1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, tetrahydrofuran, acetonitrile or the like may be used, withN,N-dimethylformamide being preferred.

In a compound represented by formula (II-A) or formula (II-B):

R¹ is a C₁₋₆ alkyl, C₁₋₆ alkenyl, C₆₋₁₀ aryl or C₇₋₁₁ aralkyl group, theC₁₋₆ alkyl group or C₁₋₆ alkenyl group optionally having 1 to 3identical or different substituents selected from the group consistingof halogen atoms and methoxy groups and the C₆₋₁₀ aryl group or C₇₋₁₁aralkyl group optionally having 1 to 3 identical or differentsubstituents selected from among halogen atoms, methyl, methoxy andnitro groups, and X is a halogen atom. Also, the two R¹ groups informula (II-B) may together constitute a cyclic carbonic acid ester withan alkylene group such as an ethylene group.

Examples for compound (II-A) include methyl chloroformate, ethylchloroformate, isopropyl chloroformate, 2-methoxy ethyl chloroformate,1-chloroethyl chloroformate, isobutyl chloroformate,2,2,2-trichloroethyl chloroformate, propyl chloroformate, 2-chloroethylchloroformate, phenyl chloroformate, 2-naphthyl chloroformate, benzylchloroformate, 4-chlorophenyl chloroformate and 4-nitrophenylchloroformate, and examples for compound (II-B) include dimethylcarbonate, diethyl carbonate, triphosgene, bis(2-chloroethyl) carbonate,diallyl carbonate, diphenyl carbonate, dibenzyl carbonate and ethylenecarbonate. As other activated reagents there may be used instead ofcompound (II-A) or compound (II-B), dicarbonic acid esters such asdi-t-butyl dicarbonate, or 1,1′-carbonyldiimidazole. Compound (II) ispreferably phenyl chloroformate.

Compound (II) may be used at 1.0 to 3.0 equivalents with respect to thenumber of moles of compound (I).

There are no particular restrictions on the base, and for example,pyridine, trimethylpyridine, dimethylpyridine, potassium hydroxide,potassium carbonate, sodium hydrogencarbonate, triethylamine,N,N-diisopropylethylamine or the like may be used, with pyridine beingpreferred.

The base may be used at 1.0 to 3.0 equivalents with respect to thenumber of moles of compound (I).

To the reaction solvent, preferably 0.5 to 2.0 equivalents of, morepreferably 1.0 to 1.5 equivalents of, and particularly preferably 1.0equivalent of water may be added relative to the molar number of thecompound (I).

The reaction time for step B will also, in general, differ depending onthe starting materials, solvent and other reagents used in the reaction,but it is preferably from 15 minutes to 24 hours.

The reaction temperature for step B will also, in general, differdepending on the starting materials, solvent and other reagents used inthe reaction, but it is preferably from −50° C. to room temperature, andmore preferably from −30° C. to 0° C.

Compound (III) is supplied to step C without isolation from the reactionmixture in step B. Cyclopropylamine is used at 1.0 to 7.2 equivalentswith respect to the number of moles of compound (II).

The reaction in step C will proceed with cyclopropylamine alone, but itwill also proceed in the co-presence of both cyclopropylamine andanother base. There are no particular restrictions on other bases, whichmay be tertiary amines such as triethylamine, N,N-diisopropylethylamineor tributylamine, or heterocyclic compounds such as pyridine. Here,cyclopropylamine may be used at 1.0 to 5.0 equivalents with respect tothe number of moles of compound (II), and other bases may be used at 1.0to 5.0 equivalents with respect to the number of moles of compound (II).

The reaction time for step C will also, in general, differ depending onthe starting materials, solvent and other reagents used in the reaction,but it is preferably from 30 minutes to 90 hours.

The reaction temperature for step C will also, in general, differdepending on the starting materials, solvent and other reagents used inthe reaction, but it is preferably from −20° C. to 40° C., and morepreferably from 0° C. to 20° C.

After the reaction is finished, the compound (IV) or a salt thereof canbe precipitated and isolated by introducing a hydrous organic solvent tothe reaction solution. The amount of the hydrous organic solvent to beintroduced can be set at a volume of 10- to 20-fold amount (v/w)relative to the mass of the compound (I). Examples of an organic solventthat can be used as the hydrous organic solvent include, but are notparticularly limited to, acetone, isopropyl acetate, ethanol,1-propanol, 2-propanol, and N,N-dimethylformamide. Examples of thehydrous organic solvent are preferably water/acetone (volume ratio 3/100to 1/20), water/isopropyl acetate (volume ratio 1/20), and water/ethanol(volume ratio 1/1), and more preferably water/acetone (volume ratio1/20). It should be noted that seed crystals may be added as required inthe case of introducing a hydrous organic solvent. Alternatively, thecompound (IV) or a salt thereof can be also precipitated and isolated byintroducing water to the reaction solution after the reaction isfinished.

The obtained crystals may be rinsed using a solvent such as water oracetone to obtain compound (IV) crystals (crude product). The crystals(crude product) may then be crystallized using a solvent such as1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, dimethylsulfoxide, 2-propanol or isopropyl acetate, for purification.

Step D is a step in which compound (IV) obtained in step C is convertedto a salt. The salt of compound (IV) is preferably a methanesulfonicacid salt.

Crystals of a salt such as4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamidemethanesulfonate can be produced by the method described in PTL 4.

More specifically, in the case of producing4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamidemethanesulfonate, for example, a methanesulfonate (the crystals (C)described in Patent Literature 4) can be produced by, after4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide,acetic acid, and methanesulfonic acid are mixed to dissolve the4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide,adding 1-propanol as a poor solvent and gradually cooling this solution.It should be noted that it is preferred that the methanesulfonatecrystals (C) as seed crystals be added together with a poor solvent andthat isopropyl acetate be added to facilitate precipitation. As the seedcrystals, the methanesulfonate crystals (C) produced according to themethod described in Patent Literature 4 or to the method disclosed inthe present specification can be used.

The amount of acetic acid added is not particularly limited, butpreferably a 5 to 10-fold amount and more preferably a 6 to 8-foldamount relative to the mass of the compound (IV) can be used.

As the amount of methanesulfonic acid added, 1.00 to 1.50 equivalents,preferably 1.05 to 1.30 equivalents, more preferably 1.05 to 1.22equivalents, and particularly preferably 1.20 equivalents relative tothe molar number of the compound (IV) can be used.

Methanesulfonic acid can be mixed with the compound (IV) at once or inportions, and after preferably 1.00 equivalent to 1.10 equivalents andmore preferably 1.05 equivalents are used, it is preferred thatpreferably additional 0.10 equivalents to 0.20 equivalents and morepreferably additional 0.15 equivalents be used relative to the molarnumber of the compound (IV).

In the case where a salt of4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamideand other acid is produced, a desired acid may be used instead ofmethanesulfonic acid. The amount of the acid added should be adjusted asappropriate by referring the amount of methanesulfonic acid added.

The reaction temperature in the step D usually differs on startingmaterials, solvents, and other reagents used in the reaction, and ispreferably 20 to 40° C. and more preferably 25 to 35° C.

As the poor solvent, methanol, ethanol, 1-propanol, 2-propanol and thelike, preferably 1-propanol can be used.

The amount of the poor solvent is not particularly limited, butpreferably a 2 to 15-fold amount and more preferably a 8 to 10-foldamount is used relative to the mass of the compound (IV).

In the case where isopropyl acetate is added, the amount is notparticularly limited, preferably a 2 to 10-fold amount and morepreferably a 5-fold amount is used relative to the mass of the compound(IV).

The cooling temperature is not particularly limited, but it ispreferably 15 to 25° C.

The crystals obtained by filtration are stirred in ethanol. The amountof ethanol to be used is not particularly limited, but preferably a 5 to10-fold amount and more preferably a 7.5-fold amount is used relative tothe mass of the compound (IV).

The crystals obtained are stirred in ethanol preferably at 20 to 60° C.for 2 to 5 hours, and preferably for 3 hours.

According to the above production method, in the methanesulfonate of thecompound (IV), the contents of the compound (A-1), the compound (I), andthe compound (C-1) can be set to 60 ppm by mass or less, 350 ppm by massor less, and 0.10% by mass or less, respectively.

In particular, the content of the compound (I) in the methanesulfonateof the compound (IV) can be reduced to 183 ppm by mass or less by usingcyclopropylamine excessively in the step C, or by performingrecrystallization of the compound (IV) before the methanesulfonate ofthe compound (IV) is synthesized.

The compound (A-1) is the starting material of the step A, but itssolubility in organic solvents is low. Accordingly, it is difficult toremove the compound (A-1) from the compound (IV) or a salt thereof byrecrystallization. However, in accordance with the production methodaccording to the present invention, the content of compound (A-1) in thecompound (IV) or a salt thereof can be reduced by undergoing multiplestages synthetic route from the step A through the step B to the step C.In particular, according to the consideration of the present inventors,since there is a possibility that the compound (A-1) exhibitsgenotoxicity, it is important to reduce the content of the compound(A-1) in the compound (IV) or a salt thereof.

It is preferred that the content of the compound (A-1) in the compound(IV) or a salt thereof be 60 ppm by mass or less based on Thresholds ofToxicological Concern (TTC) specified in “Guideline on the Limits ofGenotoxic Impurities” issued by the European Medicines Agency.

$\begin{matrix}{{{Threshold}\mspace{14mu}{of}\mspace{14mu}{toxicological}\mspace{14mu}{concern}} = {\frac{1.5\mspace{14mu}{µg}\text{/}{person}\text{/}{day}}{{{Maximum}\mspace{14mu}{tolerated}\mspace{14mu}{dose}} = {0.025\mspace{14mu} g\text{/}{day}}} = {60\mspace{14mu}{ppm}\mspace{14mu}{by}\mspace{14mu}{mass}}}} & \left\lbrack {{Expression}\mspace{14mu} 1} \right\rbrack\end{matrix}$

The compound (I) is the starting material of the step B, and theunreacted compound (I) remains as an impurity in the compound (III) oris formed by decomposition of the compound (III) or the compound (IV) ora salt thereof in the step B. In particular, when the methanesulfonateof the compound (IV) heated after dissolved in a solvent, the compound(I) is formed as a decomposition product of the compound (IV) and thelike. In accordance with the production method according to the presentinvention, the content of compound (I) in the compound (IV) or a saltthereof can be further reduced by using cyclopropylamine excessively inthe step C, or by dividing a minimum necessary amount of methanesulfonicacid and mixing the amount with the compound (IV) when a salt of thecompound (IV) is synthesized in the step D. Additionally, the content ofthe compound (I) in a salt of the compound (IV) can be further reducedby performing recrystallization of the compound (IV) to reduce thecontent of the compound (I) in the compound (IV) before the salt of thecompound (IV) is synthesized. In particular, the compound (I) is achemical substance posted on the Workplace Safety Site “Chemicalsubstances on which strong mutagenicity was recognized” of the Ministryof Health, Labour and Welfare of Japan (Public Notice No. 166 of theMinistry of Health, Labour and Welfare of Mar. 27, 2012), and it isimportant to reduce the content of the compound (I) in the compound(IV).

Since it is difficult to constantly control the content of the compound(I) in the compound (IV) or a salt thereof to be equal to or below TTC,it is preferred that the content be in the As Low As ReasonablyPracticable (ALARP) level, i.e., be 350 ppm by mass or less based on theaverage of the measured values of production lots 1 to 8 and the upperlimit of the confidence interval. According to one embodiment of theproduction method of the present invention, as shown in Table 1, thecontent of the compound (I) contained in the methanesulfonate of thecompound (IV) can be reduced to 350 ppm by mass or less. In particular,the content of the compound (I) can be reduced to 350 ppm by mass orless by appropriately combining using potassium hydroxide as the base inthe step A in the lots 5 to 8, additionally isolating the compound (I)as crystals of its anhydrate after the step A and adding water to thereaction solution in the step B in the lots 6 to 8, usingcyclopropylamine excessively in the step C and carrying outrecrystallization of the compound (IV) before the step D in the lots 5to 8, and the like.

TABLE 1 Lot Compound (I)^(a) 1 280 2 180 3 171 4 173 5 61 6 120 7 118 8114 Average 152.1 Standard deviation 65.3 Average + Upper limit of 348the confidence interval^(b) acceptance criterion ≤350 Unit: ppm by mass^(a)The quantitation limit (lower limit) is 7 ppm by mass. ^(b)The upperlimit of the confidence interval = three times standard deviation of thebatch analysis data

Since it is difficult to constantly control the content of the compound(I) in the compound (IV) or a salt thereof to be equal to or below TTC,it is preferred that the content be in the As Low As ReasonablyPracticable (ALARP) level, i.e., be 183 ppm by mass or less based on theaverage of the measured value of the production lots 5 to 10 and theupper limit of the confidence interval. In particular, the content ofthe compound (I) contained in the methanesulfonate of the compound (IV)can be further reduced to 183 ppm by mass or less as shown in Table 2 byappropriately combining using potassium hydroxide as the base in thestep A in lots 5 to 10, additionally isolating the compound (I) ascrystals of its anhydrate after the step A and adding water to thereaction solution in the step B in lots 6 to 10, using an excessiveamount of cyclopropylamine in the step C and carrying outrecrystallization of the compound (IV) before the step D in lots 5 to10, and dividing methanesulfonic acid and mixing it with the compound(IV) in the step D in lots 9 to 10, and the like.

TABLE 2 Lot Compound (I)^(a) 5 61 6 120 7 118 8 114 9 93 10  52 Average93.0 Standard deviation 30 Average + Upper limit of 183 the confidenceinterval^(b) acceptance criterion ≤183 Unit: ppm by mass ^(a)Thequantitation limit (lower limit) is 7 ppm by mass. ^(b)The upper limitof the confidence interval = three times standard deviation of the batchanalysis data

The compound (C-1) is a byproduct formed mainly in the step B. In thestep B, formation of the compound (C-1) can be suppressed moreeffectively by further adding one equivalent of water to the reactionsolution. It should be noted that, in the case where the compound(I).monohydrate is used as the starting material, the formation of thecompound (C-1) can be suppressed without addition of one equivalent ofwater.

It is preferred that the content of the compound (C-1) in the compound(IV) or a salt thereof be 0.10% by mass or less in accordance with theguidelines of ICH Q3A.

It is preferred that the purity of the compound (IV) or a salt thereofbe 98.0% by mass or more considering the batch analysis data, stabilitytest, and analytical variability.

In the case where the compound (IV) or a salt thereof is formulated, apharmaceutical composition comprising the compound (IV) or a saltthereof and an appropriate additive as a pharmaceutically acceptablecarrier is usually used. However, the above description is not intendedto deny that formulation is carried out by using only the compound (IV)or a salt thereof.

As the above additive, an excipient, a binder, a lubricant, adisintegrating agent, and the like that may be generally used in thepharmaceutical field can be used. As the above additive, these incombination as appropriate can be also used.

Examples of the above excipient include lactose, saccharose, glucose,mannitol, pregelatinized starch, and crystalline cellulose.

Examples of the above binder include methyl cellulose, hydroxypropylmethyl cellulose, and hydroxypropyl cellulose.

Examples of the above lubricant include magnesium stearate, talc,polyethylene glycol, and colloidal silica.

Examples of the above disintegrating agent include crystallinecellulose, agar, gelatin, calcium carbonate, and sodium hydrogencarbonate.

Additionally, examples of the above formulation include oral solidformulations such as tablets, powders, granules, capsules, syrups,troches, and inhalants. The formulations obtained by formulating thecompound (IV) or a salt thereof or a pharmaceutical compositioncomprising the same are usually accommodated in appropriate primarypackaging (a container or packet) and handled as a pharmaceutical. Asthe primary packaging, packaging in a shape suitable for eachformulation application can be used.

The above oral solid formulation is formulated by combining the aboveadditives as appropriate. It should be noted that coating may be appliedon the surface of the oral solid formulation as required.

The oral solid formulation can be produced in accordance with thedescription of, for example, WO 2006/030826 or WO 2011/021597. In thecase where a 5% aqueous solution (W/W) is prepared to stabilize thecompound (IV) or a salt thereof, it is preferred to use a compound ofwhich pH becomes 8 or more as a pharmaceutically acceptable carrier.Alternatively, for stabilization of the compound (IV) or a salt thereof,a carbonate of an alkaline earth metal may be used as a pharmaceuticallyacceptable carrier.

The primary packaging for the oral solid formulation is, for example, aglass or plastic bottle or jar. The plastic herein means polymers suchas high-density polyethylene (HDPE). Additionally, in the case ofaccommodating the oral solid formulation in a bottle, a drying agent,such as silica gel, can be encapsulated with the above formulation.

One embodiment of the above pharmaceutical is an HDPE bottle in whichtablets or capsules comprising the compound (IV) or a salt thereof andsilica gel are encapsulated. Specifically, an example is an HDPE bottlein which about 30 capsules comprising the compound (IV) or a saltthereof and about 2 g of silica gel are encapsulated.

Another example of the primary packaging for the oral solid formulationis blister packaging. An example of the blister packaging is pressthrough packaging (PTP). The PTP is composed of molding materials, lidmaterials, and the like.

Examples of components of the above molding materials include metalssuch as aluminum, and plastics such as polyvinyl chloride (PVC),polyvinylidene chloride (PVDC), cyclic polyolefins, polyamides, andpolypropylene (PP). The molding material may be a monolayer material ofa single component, or may be a laminate material of a plurality ofcomponents, such as an aluminum laminate film. The lid material iscomposed of a supporting material such as aluminum or plastic, and, asrequired, a heat-seal agent and the like.

An embodiment of the PTP is, for example, PTP composed of a moldingmaterial of an aluminum laminate film and a lid material of aluminum, orPTP composed of a molding material made of plastic and a lid material ofaluminum. To such PTP, secondary packaging (pillow packaging) may beapplied using polyethylene or aluminum as required. Additionally, adrying agent may be used with PTP in the pillow packaging.

One embodiment of the above pharmaceutical is PTP in which tablets orcapsules comprising the compound (IV) or a salt thereof areaccommodated, wherein the PTP is composed of an aluminum laminate filmand aluminum.

The above bottle or the above PTP may be accommodated with a packageinsert of the pharmaceutical in a box and the like, as a final packagingform.

In the oral solid formulation comprising the compound (IV) or a saltthereof, the compound (I) increases by 0.02% at most during storage inacceleration test, as shown in examples described below. In other words,as shown in Table 1, when the oral solid formulation comprising thecompound (IV) or a salt thereof in which the content of the compound (I)is 350 ppm by mass or less, is stored under storage conditions of theacceleration test described below or during storage at room temperaturefor three years, the content of the compound (I) could be kept 0.06% bymass or less in the oral solid formulation.

Accordingly, one aspect of the present invention is an oral solidformulation which comprises the compound (IV) or a salt thereof and apharmaceutically acceptable carrier and in which the content of thecompound (I) is 0.06% by mass or less.

Alternatively, as shown in Table 2, when the oral solid formulationcomprising the compound (IV) or a salt thereof in which the content ofthe compound (I) is 183 ppm by mass or less, is stored under storageconditions of the acceleration test described below or during storage atroom temperature for three years, the content of compound (I) could bekept 0.04% by mass or less or 0.040% by mass or less in the oral solidformulation.

Accordingly, one aspect of the present invention is an oral solidformulation which comprises the compound (IV) or a salt thereof and apharmaceutically acceptable carrier and in which the content of thecompound (I) is 0.04% by mass or less or 0.040% by mass or less.

In the case of using the compound (IV) or a salt thereof for productionof a pharmaceutical, the amount used differs on symptoms, ages, andadminister forms, but usually for an adult, 100 μg to 10 g isadministered once a day, or used in portions several times a day.

EXAMPLES

The invention will now be further explained by examples, with theunderstanding that the invention is not limited to these examples.

Example 1: 4-(4-Amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide

A mixture of 43.5 kg of 4-amino-3-chlorophenol hydrochloride, 53.8 kg ofa 48.5 w/w % potassium hydroxide aqueous solution, 44.0 kg of4-chloro-7-methoxy-quinoline-6-carboxamide and 396 L of dimethylsulfoxide was stirred at 70° C. for 20 hours under a nitrogenatmosphere. After adding water-containing acetone (acetone: 220 L,purified water: 440 L) to the reaction mixture at 55° C., the mixturewas cooled to 8° C. and the deposited precipitate was filtered. Theprecipitate was rinsed with an aqueous acetone solution, and theobtained solid was dried under reduced pressure to obtain 59.3 kg of4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide (yield:93%).

Example 2:4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide

To a mixture of 26.0 kg of4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide, 13.2 kgof pyridine, 1.36 kg of water and 196.0 L of N,N-dimethylformamide therewas added 26.6 kg of phenyl chloroformate at −20° C. under a nitrogenatmosphere, and the mixture was stirred for 3 hours. Next, 19.4 kg ofcyclopropylamine was further added at 8° C. and the mixture was stirredfor 15 hours. After adding 13.0 L of water and 261.0 L of acetone to thereaction mixture, the deposited precipitate was filtered. Theprecipitate was rinsed with acetone, and the obtained solid was driedunder reduced pressure to obtain 28.7 kg of a crude product of the titlecompound (89% yield). This was crystallized from 359.6 L of1,3-dimethyl-2-imidazolidinone and 575.0 L of 2-propanol, to obtain 25.7kg of compound (IV) (90% yield).

In Examples 1 and 2, the total yield was 83% through the two steps up toobtaining the crude product of compound (IV), in terms of the startingmaterial of compound (I), and this was a high yield compared to theyield in the production method of PTL 1 (three steps, 25.5%). Also,crystallization of compound (IV) allowed a higher purity compound (IV)to be obtained at a yield of 90%.

Example 3:4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamidemethanesulfonate

In a mixed solution of methanesulfonic acid (5.44 kg) and acetic acid(150 L) was dissolved4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide(23.0 kg) at 20° C. to 35° C. Methanesulfonic acid (777 g) was furtheradded, the solution was filtered at a temperature of 35° C. or less, andthe filter paper was washed with acetic acid (11.5 L). To the filtrate,1-propanol (46.0 L) and seed crystals (230 g) were added at 25° C. to45° C., and 1-propanol (161 L) and isopropyl acetate (115 L) was furtheradded dropwise at 25° C. to 45° C. The mixed solution was cooled to 15°C. to 25° C., and subsequently, the deposited crystals were filtered andwashed with a mixed solution of 1-propanol and isopropyl acetate(1-propanol concentration: 33 v/v %). To the resulting wet crystals,ethanol (173 L) was added and stirred at 20° C. to 60° C. for threehours. After the crystals were collected by filtration and washed withethanol, the crystals were dried under reduced pressure at a temperatureof 80° C. or less to thereby obtain4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamidemethanesulfonate (27.5 kg, yield: 94%). Example 4:4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide.monohydrate

A mixture of 4-amino-3-chlorophenol hydrochloride (593.4 g), a 48.7 w/w% potassium hydroxide aqueous solution (730.6 g),4-chloro-7-methoxy-quinoline-6-carboxamide (600.0 g), anddimethylsulfoxide (5.4 L) was stirred under nitrogen atmosphere at 70°C. for 21 hours. After 3.0 g of seed crystals was introduced into thereaction solution, hydrous acetone (acetone: 3 L, purified water: 6 L)was added at 55° C. and cooled to 8° C., and the precipitated depositwas filtered. The deposit was washed with hydrous acetone, and the solidobtained using a rotary evaporator was dried at 60° C. under reducedpressure to thereby obtain4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide.monohydrate(862.7 g, yield: 94%).

Example 5:4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide

To a mixture of4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide.monohydrate(800 g), pyridine (524.8 g), and N,N-dimethylformamide (8 L), phenylchloroformate (865.6 g) was added under nitrogen atmosphere at −20° C.and stirred for one hour. Additionally, cyclopropylamine (757.6 g) wasadded and stirred at 8° C. for 18 hours. To the reaction solution, water(8 L) was added, and the precipitated deposit was filtered. The depositwas washed with hydrous N,N-dimethylformamide and ethanol, and theresulting solid was dried under reduced pressure to thereby obtain acrude product of the title compound (910 g, yield: 96%). Five hundredgrams of the crude product was crystallized from1,3-dimethyl-2-imidazolidinone (6250 mL) and 2-propanol (10 L) tothereby obtain the compound (IV) (450 g, yield: 90%).

Purity Test 1

As for the precipitated crude product of the compound (IV) obtained inExample 2, the compound (IV) obtained in accordance with the productionmethod described in Patent Literatures 1, and the precipitated crudeproduct of the compound (IV) obtained in accordance with the productionmethods described in Patent Literatures 2, 3, 4, and 5, their puritieswere analyzed by liquid chromatography and each compared. As shown inTable 3, the content of the compound (IV) produced in Example 2 washigher than the content of the compound (IV) obtained in accordance withthe production methods described in Patent Literatures 1 to 5 washigher, and the total content of impurities was lower.

The results are shown in Table 3.

TABLE 3 Production method Production Production methods method describedin described in Patent Patent Literatures 2, Content Example 2^(a)Literature 1^(b) 3, 4, and 5^(c) Area % Total impurities 0.355 5.391.702 Compound (IV) 99.645 94.61 98.298 % by Total impurities 0.17 4.51.3 mass Compound (IV) 98.5 91.9 96.3 ^(a)Measured by use of theprecipitated crude product of the compound (IV) obtained in Example 2^(b)Measured by use of the compound (IV) obtained by the productionmethod described in Patent Literature 1 (Example 368) ^(c)Measured byuse of the precipitated crude product of the compounds (IV) obtained bythe production methods described in Patent Literature 2 (ReferenceExample 3), Patent Literature 3 (Example 4), Patent Literature 4(Production Example 3) and Patent Literature 5 (Example 1a)

Calculation of the area % in Table 3 was performed as follows. The peakarea of the peaks derived from the sample on the chromatogram obtainedunder the following measurement conditions was calculated, the peak areaof each peak was divided by the total to thereby take the total of thefigures of the peaks corresponding to impurities as the total content ofthe impurities and the figure corresponding to the compound (IV) as thecontent of the compound (IV).

Additionally, calculation of % by mass in Table 3 was performed asfollows. First, as for the content of the compound (IV), by using astandard of the compound (IV) obtained by crystallization as an externalcontrol and comparing the peak area of the peaks each corresponding tothe compound (IV) in the standard and in the sample, the content of thecompound (IV) in the sample was calculated. Subsequently, in order tocompensate the difference in the absorbance of each impurity per unitmass, after each impurity was identified in accordance with theprocedure described in Purity test 2 and a sample of each impurity wassynthesized, the absorbance (sensitivity coefficient) of each impuritywas determined when the absorbance of the compound (IV) was set to 1.Then, by use of the peak areas and sensitivity coefficients of theimpurities in the sample, the mass of each impurity (%) was calculated,and the total of the impurities detected to exceed 0.05% by mass wastaken as the total content of impurities.

Liquid Chromatography Measuring Conditions

Detector: Ultraviolet absorptiometer (measuring wavelength: 252 nm).

Column: YMC-Pack ProC18 (YMC Inc.), inner diameter: 4.6 mm, length: 15cm, filler particle diameter: 3 μm

Column temperature: Constant temperature near 25° C.

Mobile phase: Solution A and solution B having the followingcompositions were eluted with the linear gradient shown in Table 2.

Solution A: Water/acetonitrile/70% perchloric acid mixture (990:10:1,v/v/v)

Solution B: Water/acetonitrile/70% perchloric acid mixture (100:900:1,v/v/v)

Flow rate: 1.0 mL/min

Injection rate: 10 μL

Sample rack temperature: Constant temperature near 15° C.

Area measurement range: 45 minutes

TABLE 4 Time Proportion of solution B in mobile phase (min) (vol %) 0 1535 40 42 100 45 100 45.01 15 55 STOP

It should be noted that the quantitation limits (lower limits) of thecompound (A-1), the compound (I), and the compound (C-1) under themeasurement conditions of Purity test 1 are each 0.0020% by mass (20 ppmby mass), 0.0020% by mass (20 ppm by mass), and 0.0022% by mass (22 ppmby mass).

Purity Test 2

Under the measurement conditions of Purity test 1, each retention timeof the compound (A-1), the compound (I), the compound (C-1), and thecompound (IV) was compared. The “relative retention time” shown in Table5 means the relative retention time of the compound (A-1), the compound(I), and the compound (C-1) relative to the compound (IV). That is, thevalue obtained from dividing the retention time of the peak derived fromeach compound on the chromatogram obtained under the measurementconditions of Purity test 1 by the retention time of the peak obtainedby injecting the compound (IV) was described as the “relative retentiontime”.

TABLE 5 Compound Relative retention time Compound (I) 0.74 Compound(A-1) 0.26 Compound (C-1) 1.86

Under the above measurement conditions, each compound was identified bythe fact that its elution time in HPLC corresponded with the elutiontime of the sample. It should be noted that the samples of each compoundwere separately synthesized and the chemical structures were eachdetermined based on their ¹H-NMR and MS spectra.

Compound (C-1):1-{2-Chloro-4-[(6-cyano-7-methoxy-quinolin-4-yl)oxy]phenyl}-3-cyclopropylurea

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.66 (2H, m), 2.57 (1H,dtt, J=3.4, 7 Hz), 4.05 (3H, s), 6.58 (1H, d, J=5 Hz), 7.20 (1H, d, J=3Hz), 7.25 (1H, dd, J=3.9 Hz), 7.49 (1H, d, J=3 Hz), 7.58 (1H, s), 7.98(1H, s), 8.28 (1H, d, J=9 Hz), 8.72 (1H, s), 8.73 (1H, d, J=5 Hz).

Subsequently, as for the compound (IV) obtained in Example 2 and thecompound (IV) obtained by Patent Literatures 2, 3, 4, and 5, the contentof the compound (A-1) was measured by liquid chromatography.Consequently, as shown in Table 6, the content of the compound (A-1) was1311 ppm by mass in the compound (IV) obtained by the production methodsdescribed in Patent Literatures 2, 3, 4, and 5, whereas the contentdecreased to 20 ppm by mass or less in the compound (IV) obtained inExample 2.

TABLE 6 Production method Production methods described in Patent Example2 Literatures 2, 3, 4, and 5** Content of the ≤20 ppm by mass 1311 ppmby mass compound (A-1) *Each measured by use of the precipitated crudeproduct from the reaction solution **Production methods described inPatent Literature 2 (Reference Example 3), Patent Literature 3 (Example4), Patent Literature 4 (Production Example 3) and Patent Literature 5(Example 1a)

As for the compound (IV) obtained in Example 2 and the compound (IV)obtained by the production method described in Patent Literature 1, thecontent of the compound (C-1) was measured by liquid chromatography.Consequently, as shown in Table 7, the content of the compound (C-1) was3.37% by mass in the compound (IV) obtained by the production methoddescribed in Patent Literature 1, whereas the content of the compound(C-1) decreased to 0.05% by mass or less in the compound (IV) obtainedin Example 2.

TABLE 7 Production method Production method described in Patent Example2* Literature 1** Content of the compound (C-1) ≤0.05% by mass 3.37% bymass *Measured by use of the precipitated crude product of the compound(IV) obtained in Example 2 **Measured by use of the compound (IV)obtained by the production method described in Patent Literature 1(Example 368)

Purity Test 3

As for the methanesulfonate of the compound (IV) obtained in Example 3,the compound (C-1) under the following measurement conditions A and thecompound (A-1) and compound (I) under the following measurementconditions B were each detected. In particular, as for the compound(A-1) and compound (I), measurement was able to be performed with goodsensitivity by an external standard method in which standard solutionsprepared from those standards were used, under the following conditions.It should be noted that the purity of the methanesulfonate of thecompound (IV) obtained in Example 3 was 99.3% by mass.

Liquid Chromatography Measuring Conditions

Detector: Ultraviolet absorptiometer (measuring wavelength: 252 nm).

Column: YMC-Pack ProC18 (YMC Inc.), inner diameter: 4.6 mm, length: 7.5cm, filler particle diameter: 3 μm

Column temperature: Constant temperature near 40° C.

Mobile phase: Solution A and solution B having the followingcompositions were eluted with the linear gradient shown in Table 8.

Solution A: Water/acetonitrile/70% perchloric acid mixture (990:10:1,v/v/v)

Solution B: Water/acetonitrile/70% perchloric acid mixture (100:900:1,v/v/v)

Flow rate: 1.0 mL/min

Injection rate: 10 μL

Sample rack temperature: Constant temperature near 15° C.

Area measurement range: 30 minutes

TABLE 8 Time Proportion of solution B in mobile phase (min) (vol %) 0 525 55 30 100 35 100 35.01 5 45 STOP

It should be noted that the quantitation limit (lower limit) of thecompound (C-1) under the above measurement conditions A in Purity test 3is 0.01% by mass.

Liquid Chromatography Measuring Conditions

Detector: Ultraviolet absorptiometer (measuring wavelength: 252 nm).

Column: YMC-Pack ProC18 (YMC Inc.), inner diameter: 4.6 mm, length: 7.5cm, filler particle diameter: 3 μm

Column temperature: Constant temperature near 40° C.

Mobile phase: Solution A and solution B having the followingcompositions were eluted with the linear gradient shown in Table 9.

Solution A: Water/acetonitrile/70% perchloric acid mixture (990:10:1,v/v/v)

Solution B: Water/acetonitrile/70% perchloric acid mixture (100:900:1,v/v/v)

Flow rate: 1.0 mL/min

Injection rate: 5 μL

Sample rack temperature: Constant temperature near 15° C.

Area measurement range: 13 minutes

TABLE 9 Time Proportion of solution B in mobile phase (min) (vol %) 0 515 35 15.01 100 20 100 20.01 5 30 STOP

It should be noted that the quantitation limits (lower limits) of thecompound (I) and compound (A-1) are 7 ppm by mass and 12 ppm by massrespectively under the measurement conditions B.

The contents of each compound obtained are shown in Table 10.

TABLE 10 Impurity Content Compound (I) 52 ppm by mass Compound (A-1) 12ppm by mass ≥ Compound (C-1) 0.05% by mass ≥

Example 6

Capsules of 4-mg capsules and 10-mg capsules were produced by using themethanesulfonate of the compound (IV) shown in Table 1 or Table 2 andusing D-mannitol, precipitated calcium carbonate, low-substitutedhydroxypropyl cellulose, crystalline cellulose, hydroxypropyl cellulose,talc, and the like. It should be noted that “a 4-mg capsule” means acapsule comprising 4 mg of the compound (IV) in the capsule. The mass ofthe granules which is the content of the capsule is 100 mg per capsule.The contents of the compound (I) (% by mass) relative to the total massof the capsule at the time of producing a capsule (also referred to as“the initial content”) are shown in Table 11.

TABLE 11 Content of the compound (I) (% by mass) Lot 10 mg Capsule 4 mgCapsule 1 0.03 0.03 3 0.02 0.02 5 0.00 0.00 6 0.01 0.01 7 0.01 0.01 80.02 —

By using 4-mg and 10-mg capsules of the compound (IV) produced with themesylate of the compound (IV) in the lot 5, 6, or 7 (the mass of thegranules which is the content of the capsule is 100 mg per capsule),acceleration test (40° C./75% RH, PTP (molding material: aluminumlaminate film (polyamide/aluminum/polyvinyl chloride), lid material:aluminum foil)) and long-term storage test (25° C./60% RH, PTP (moldingmaterial: aluminum laminate film (polyamide/aluminum/polyvinylchloride), lid material: aluminum foil)) were performed.

In the acceleration test on 4-mg and 10-mg capsules, the contents of thecompound (I) increased by 0.02% by mass and 0.01% by mass respectivelyat most compared with the initial content. Additionally the content ofthe compound (I) in the long-term storage test for 24 month slightlyincreased compared with the initial content. The increase in the contentof the compound (I) in the long-term storage test was smaller than theeffective figure of the quantitation limit, and was specifically 0.003%by mass to 0.004% by mass. The measurement of the contents of thecompound (I) in these capsules were performed by liquid chromatography(detection limit (lower limit): 0.0020% by mass), and the quantitationlimit (lower limit) was 0.01% by mass.

The invention claimed is:
 1. A methanesulfonate salt of a compoundrepresented by formula (IV), wherein the content of a compoundrepresented by formula (I) is 183 ppm by mass or less


2. The methanesulfonate salt of a compound represented by formula (IV)according to claim 1, wherein the content of the methanesulfonate saltof a compound represented by formula (IV) is 98.0% by mass or more. 3.The methanesulfonate salt of a compound represented by formula (IV)according to claim 1, wherein the content of the compound represented byformula (I) is determined by HPLC.